Reinvesting the cellular properties of human amniotic epithelial cells and their therapeutic innovations

Abstract

Human amniotic epithelial cells (hAECs) have shown promising therapeutic effects in numerous studies on various diseases due to their properties such as low immunogenicity, immunomodulation, paracrine effect, and no teratoma formation in vivo. Nevertheless, there are still many problems in archiving the large-scale clinical application of hAECs, ranging from the vague definition of cell properties to the lack of clarification of the motion of actions in cell therapies, additionally, to the gap between cell quantities with limited proliferation capacity. This review provides a detailed overview of hAECs in the aspects of the lineage development of amniotic epithelial cell, cell characteristics and functional roles, ex vivo cell cultivation and expansion systems, as well as their current status and limitations in clinical applications. This review also discusses the advantages, limitations and feasibility of hAECs, and anticipates their prospects as cell therapy products, with the aim of further promoting their clinical applications.

Keywords: cell expansion; cell therapy; clinical trials; epithelial-mesenchymal plasticity (EMP); human amniotic epithelial cells (hAECs); therapeutic mechanisms.

Figure 1

Schematic representation of early embryonic development and the structure of human amniotic membrane. (A). A zygote goes through rapid divisions. At the morula stage, the cells exhibit differential division rates, resulting in the formation of inner cell mass (ICM) and trophectoderm. ICM further differentiates into epiblast and hypoblast, forming the bilaminar disk prior to the embryo implantation. Amniotic sac is instantly developed during peri-implantation, which precedes the formation of primitive streak, the hallmark of gastrulation. Hypoblast develops into yolk sac to provide nutrients for the early embryo development before the maturation of placenta. Trophectoderm, on the other side, forms trophoblast and then eventually develops into placenta. a-d shows the stages of early embryonic development. (B). Human amniotic membrane is composed of 5 layers: 1) an epithelial monolayer, 2) a basement membrane layer, 3) a compact layer, 4) a fibroblast layer and 5) a spongy layer. hAECs are arranged on the basement membrane which is mostly made up by collagen (type III, IV, V), fibronectin and laminin. The compact layer is the main fibrous skeleton containing collagen (type I, III, V, VI) and fibronectin. Human amniotic mesenchymal cells locate in the fibroblast layer consisting of collagen (type I, III, IV), fibronectin, laminin and nidogen. The spongy layer as the intermediates between amnion and chorion are mainly comprised collagen (type I, III, IV) and proteoglycans.

Figure 2

Signaling pathways involved in epithelial-mesenchymal transition (EMT). EMT is a biological process that allows an epithelial cell to undergo phenotypic and biochemical transitions that enable it to present a mesenchymal cell phenotype, losing the interaction with basement membrane while gaining the characteristics like migratory capacity and invasiveness. MET is, on the other side, an exact reversed process. The epithelial and mesenchymal cell markers commonly used are listed. Co-expression of the two sets of distinct markers during EMT indicates an intermediate/hybrid state, termed as EMP. Recent studies have shown that during embryogenesis and epithelia homeostasis, certain epithelial cells appear to be plastic and thus able to move back and forth between epithelial and mesenchymal states via the processes of EMT and MET. The activation of TGF-β signaling has been proved to induce the initiation of EMT.

Figure 3

Pre-clinical and clinical studies of hAECs on diseases treatment. A schematic overview of hAECs on various diseases treatment and the underlying potential mechanisms.